Aminoalkyl substituted (benzodioxan, benzofuran or benzopyran) derivatives

ABSTRACT

The present invention concerns compounds of formula (I) 
                 
 
a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, wherein —Z 1 —Z 2 — is a bivalent radical; R 1 , R 2  and R 3  are each independently selected from hydrogen, C 1-6 alkyl, hydroxy, halo and the like; or when R 1  and R 2  are on adjacent carbon atoms, R 1  and R 2  taken together may form a bivalent radical of formula; Alk 1  and Alk 2  are optionally substituted C 1-6 alkanediyl; R 6  is hydrogen or phenylmethyl; R 5  is a radical of formula 
                 
 
wherein n is 1 or 2; p 1  is 0, and p 2  is 1 or 2; or p 1  is 1 or 2, and p 2  is 0; X is oxygen, sulfur or ═NR 9 ; Y is oxygen or sulfur; R 7  is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or phenylmethyl; R 8  is C 1-6 alkyl, C 3-6 cycloalkyl phenyl or phenylmethyl; R 9  is cyano, C 1-6 alkyl, C 3-6 cyclo-alkyl, C 1-6 alkyloxycarbonyl or aminocarbonyl; R 10  is hydrogen or C 1-6 alkyl; and Q is a bivalent radical. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to impaired fundic relaxation.

The present invention is concerned with novel aminoalkylchromanecompounds having fundic relaxation properties. The invention furtherrelates to methods for preparing such compounds, pharmaceuticalcompositions comprising said compounds as well as the use as a medicineof said compounds.

Structurally related aminomethylchromane derivatives are disclosed inU.S. Pat. No. 5,541,199 as selective autoreceptor agonists useful asantipsychotic agents. Other structurally related aminomethylchromanderivatives having affinity for cerebral 5-hydroxytryptamine receptorsof the 5-HT₁ type and therefore suitable for the treatment of disordersof the central nervous system are disclosed in U.S. Pat. No. 5,137,901.

EP-0,546,388, published on 16 Jun. 1993, discloses structurally relatedaminomethylchroman derivatives having affinity for cerebral5-hydroxytryptamine receptors of the 5-HT₁ type and for dopaminereceptors of the D₂-type. EP-0,628,310, published on 14 Dec. 1994,encompasses the use of the same aminomethylchroman derivatives for theinhibition of HIV-protease.

DE-2,400,094, published on 18 Jul. 1974, discloses1-[1-[2-(1,4benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl-2-benzimidazolinonespossessing blood pressure lowering activity.

DE-2,852,945, published on 26 Jun. 1980, disclosesbenzodioaxanylhydroxyethyl-piperidylimidazolidinones havingantihypertensive activity.

EP0,004,358, published on 3 Oct. 1979, disclosesN-oxacycloalkylalkylpiperidines useful as antidepressants andpsychostimulants.

EP-0,048,218, published on 24 Mar. 1982, discloses N-oxides ofN-oxacycloalkylalkylpiperidines having antidepressant activity.

WO-93/17017, published on 2 Sep. 1993, discloses [(benzodioxane,benzofuran or benzopyran)alkylamino]alkyl-substituted guanidine asselective vasoconstrictors useful to treat conditions related tovasodilatation such as, e.g., migraine, cluster headache and headacheassociated with vascular disorders.

WO-95/053837, published on 23 Feb. 1995, encompassesdihydrobenzopyran-pyrimidine derivatives also having vasoconstrictiveactivity.

Other structurally related aminomethylchroman derivatives are disclosedin WO-97/28157, published on 7 Aug. 1997, as α₂-adrenergic receptorantagonists useful in the treatment of degenerative neurologicalconditions.

The compounds of the present invention differ from the cited art-knowncompounds structurally, by the nature of the R⁵ substituent, andpharmacologically by the fact that, unexpectedly, these compounds havefundic relaxation properties. Furthermore, the compounds of the presentinvention have additional beneficial pharmacological properties in thatthey have little or no vasoconstrictor activity.

During the consumption of a meal the fundus, i.e. the proximal part ofthe stomach, relaxes and provides a “reservoir” function. Patientshaving an impaired adaptive relaxation of the fundus upon food ingestionhave been shown to be hypersensitive to gastric distension and displaydyspeptic symptoms. Therefore, it is believed that compounds which areable to normalize an impaired fundic relaxation are useful to relievepatients suffering from said dyspeptic symptoms.

The present invention concerns compounds of formula (I)

-   -   a stereochemically isomeric form thereof, an N-oxide form        thereof, a pharmaceutically acceptable acid addition salt        thereof, or a quaternary ammonium salt thereof, wherein    -   Alk¹ is C₁₋₄alkylcarbonyl, C₁₋₄alkylcarbonylC₁₋₄alkyl, carbonyl,        carbonylC₁₋₄alkyl, or C₁₋₆alkanediyl optionally substituted with        hydroxy, halo, amino, hydroxyC₁₋₄alkyl, C₁₋₄alkyloxy,        C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkylcarbonyloxy,        C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, or        C₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy,    -   Alk² is C₁₋₄alkylcarbonylC₁₋₄alkyl; C₁₋₆alkanediyl substituted        with hydroxy, halo, amino, hydroxyC₁₋₄alkyl, C₁₋₄alkyloxy,        C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl,        C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, or        C₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy;        C₃₋₈cycloalkanediyl optionally substituted with halo, hydroxy,        hydroxyC₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyloxyC₁₋₄alkyl,        C₁₋₄alkyloxycarbonyl,        C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, or        C₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy;    -   —Z¹—Z²— is a bivalent radical of formula        —O—CH(R⁴)—CH₂—  (a-1),        —O—CH(R⁴)—CH₂—O—  (a-2),        —O—CH(R⁴)—CH₂—S—  (a-3),        —O—CH(R⁴)—CH₂—CH₂—  (a-4),        —O—CH(R⁴)—CH₂—CH₂—CH₂—  (a-5),        —O—C(R⁴)═CH—  (a-6),        —O—C(R⁴)═CH—CH₂—  (a-7),        —O—C(R⁴)═CH—CH₂—CH₂—  (a-8), or        —O—CH(R⁴)—CH═CH—  (a-9),        -   wherein optionally one or two hydrogen atoms on the same or            a different carbon atom may be replaced by hydroxy;    -   R¹, R² and R³ are each independently selected from hydrogen,        C₁₋₆alkyl, C₃₋₆alkenyl, C₁₋₆alkyloxy, trihalomethyl,        trihalomethoxy, halo, hydroxy, cyano, nitro, amino,        C₁₋₆alkylcarbonylamino, C₁₋₆alkyloxycarbonyl,        C₁₋₄alkylcarbonyloxy, aminocarbonyl, mono- or        di(C₁₋₆alkyl)aminocarbonyl, aminoC₁₋₆alkyl, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, or        C₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, or    -   when R¹ and R² are on adjacent carbon atoms, R¹ and R² taken        together may form a bivalent radical of formula

—CH₂—CH₂—CH₂— (b-1), —O—CH₂—CH₂— (b-6), —CH₂—CH₂—CH₂—CH₂— (b-2),—O—CH₂—CH₂—O— (b-7), —CH₂—CH₂—CH₂—CH₂—CH₂— (b-3), —O—CH₂—CH₂—CH₂— (b-8),—CH═CH—CH═CH— (b-4), —O—CH₂—CH₂—CH₂—CH₂— (b-9), —O—CH₂—O— (b-5),

-   -   -   wherein optionally one or two hydrogen atoms on the same or            a different carbon atom may be replaced by hydroxy,            C₁₋₄alkyl or CH₂OH;

    -   R⁴ is hydrogen, C₁₋₆alkyl, phenylmethyl, hydroxyC₁₋₄alkyl,        C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl,        C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyl,        C₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, or a direct        bond when the bivalent radical —Z¹—Z²— is of formula (a-6),        (a-7) or (a-8);

    -   R⁶ is hydrogen, C₁₋₆alkyl, C₁₋₄alkylcarbonyl,        C₁₋₄alkyloxycarbonyl, phenylmethyl, C₁₋₄alkylaminocarbonyl,        C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyl, or        C₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy;

    -   R⁵ is a radical of formula        -   wherein n is 1 or 2;        -   p¹ is 0, and p² is 1 or 2; or p¹ is 1 or 2, and p² is 0;        -   X is oxygen, sulfur, NR⁹ or CHNO₂;        -   Y is oxygen or sulfur;

    -   R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl or        phenylmethyl;

    -   R⁸ is C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl or phenylmethyl;

    -   R⁹ is cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkyloxycarbonyl or        aminocarbonyl;

    -   R¹⁰ is hydrogen or C₁₋₆alkyl;

    -   or R⁹ and R¹⁰ taken together with the nitrogen atom to which        they are attached may form a pyrrolidinyl, piperidinyl,        homopiperidinyl, piperazinyl, or morpholinyl group, optionally        substituted with C₁₋₄alkyl or C₁₋₄alkyloxy; and

    -   Q is a bivalent radical of formula

—CH₂—CH₂— (d-1), —CO—CH₂— (d-6), —CH₂—CH₂—CH₂— (d-2), —(CH₂)₂—CO— (d-7),—CH₂—CH₂—CH₂—CH₂— (d-3), —CO—(CH₂)₂— (d-8), —CH═CH— (d-4), —CO—CH₂—CO—(d-9), —CH₂—CO— (d-5), —CH₂—CO—CH₂— (d-10),

-   -   -   wherein optionally one or two hydrogen atoms on the same or            a different carbon atom may be replaced by C₁₋₄alkyl,            hydroxy or phenyl, or

    -   Q is a bivalent radical of formula

As used in the foregoing definitions halo is generic to fluoro, chloro,bromo and iodo; C₁₋₄alkyl defines straight and branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as, forexample, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl andthe like; C₁₋₆alkyl is meant to include C₁₋₄alkyl and the higherhomologues thereof having 5 or 6 carbon atoms, such as, for example,2-methylbutyl, pentyl, hexyl and the like; C₃₋₆cycloalkyl is generic tocyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C₃₋₆alkenyl definesstraight and branched chain unsaturated hydrocarbon radicals having from3 to 6 carbon atoms, such as propenyl, butenyl, pentenyl or hexenyl;C₁₋₂alkanediyl defines methylene or 1,2-ethanediyl; C_(1,3)alkanediyldefines bivalent straight or branched chain hydrocarbon radicalscontaining from 1 to 3 carbon atoms such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, and the branched isomers thereof;C₁₋₅alkanediyl defines bivalent straight or branched chain hydrocarbonradicals containing from 1 to 5 carbon atoms such as, for example,methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl, and the branched isomers thereof; C₁₋₆alkanediylincludes C₁₋₅alkanediyl and the higher homologues thereof having 6carbon atoms such as, for example, 1,6-hexanediyl and the like. The term“CO” refers to a carbonyl group.

Some examples of the R⁵ moiety are:

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E or Z-stereochemistry at said double bond.Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

In compounds of formula (I) wherein the bivalent radical —Z¹—Z²— is offormula (a-6), (a-7) or (a-8) the substituent R⁴ is a direct bond to the—Alk¹—NR⁶—Alk²—R⁵ moiety.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid. Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

Quaternary ammonium salts of compounds of formula (I) as used hereindefines which the compounds of formula (I) are able to form by reactionbetween a basic nitrogen of a compound of formula (I) and an appropriatequaternizing agent, such as, for example, an optionally substitutedalkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide orbenzyliodide. Other reactants with good leaving groups may also be used,such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, andalkyl p-toluenesulfonates. A quaternary ammonium salt has a positivelycharged nitrogen. Pharmaceutically acceptable counterions includechloro, bromo, iodo, trifluoroacetate and acetate. The counterion ofchoice can be made using ion exchange resin columns.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The N-oxide forms of the compounds of formula (I), which may be preparedin art-known manners, are meant to comprise those compounds of formula(I) wherein a nitrogen atom is oxidized to the N-oxide.

Interesting compounds are those compounds of formula (I) wherein one ormore of the following restrictions apply:

-   -   a) the bivalent radical —Z¹—Z²— is of formula (a-1), or (a-6);        or    -   b) the bivalent radical —Z¹—Z²— is of formula (a-2), (a-3),        (a-4), or (a-9); in particular the bivalent radical —Z¹—Z²— is        of formula (a-3) or (a-4); or    -   c) the bivalent radical —Z¹—Z²— is of formula (a-4);    -   d) R¹, R² and R³ are each independently selected from hydrogen,        C₁₋₆alkyl, hydroxy or halo;    -   e) R⁴ is hydrogen;    -   f) Alk¹ is C₁₋₂alkanediyl optionally substituted with hydroxy,        in particular Alk¹ is —CH₂—;    -   g) Alk² is C₁₋₃alkanediyl substituted with hydroxy, in        particular Alk² is —CH₂—CHOH—CH₂—; and/or    -   h) R⁶ is hydrogen of phenylmethyl.

Particular compounds of formula (I) are those compounds of formula (I)wherein the bivalent radical —Z¹—Z²— is of formula —CH₂—CH₂— (a-4).

Preferred compounds are those compounds of formula (I) wherein R⁵ is aradical of formula (c-1) wherein X is oxygen, and Q is a radical offormula (d-2) or (d-5).

More preferred compounds are those compounds of formula (I) wherein R⁴is hydrogen; Alk¹ is —CH₂—; Alk² is —CH₂—CHOH—CH₂—; R⁶ is hydrogen; R⁵is a radical of formula (c-1) wherein X is oxygen, R⁷ is hydrogen, and Qis (d-2).

Other more preferred compounds are those compounds of formula (I)wherein R⁴ is hydrogen; Alk¹ is —CH₂—; Alk² is —CH₂—CHOH—CH₂—; R⁶ ishydrogen; R⁵ is a radical of formula (c-1) wherein X is oxygen, R⁷ ishydrogen, and Q is (d-5).

Still other preferred compounds are those compounds of formula (I)wherein R⁴ is hydrogen; Alk¹ is —CHOH—CH₂—; Alk² is —CH₂—CHOH—CH₂—; R⁶is hydrogen; R⁵ is a radical of formula (c-1) wherein X is oxygen, R⁷ ishydrogen, and Q is (d-2).

Most preferred compound is

-   -   1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-2-hydroxypropyl]-2,4-imidazolidinedione;        a stereoisomeric form or a pharmaceutically acceptable acid        addition salt thereof.

The compounds of the present invention can generally be prepared byalkylating an intermediate of formula (III) with an intermediate offormula (II), wherein W is an appropriate leaving group such as, forexample, halo, e.g. fluoro, chloro, bromo, iodo, or in some instances Wmay also be a sulfonyloxy group, e.g. methanesulfonyloxy,benzenesulfonyloxy, trifluoromethanesulfonyloxy and the like reactiveleaving groups. The reaction can be performed in a reaction-inertsolvent such as, for example, acetonitrile or tetrahydrofuran, andoptionally in the presence of a suitable base such as, for example,sodium carbonate, potassium carbonate, calciumoxide or triethylamine.Stirring may enhance the rate of the reaction. The reaction mayconveniently be carried out at a temperature ranging between roomtemperature and the reflux temperature of the reaction mixture and, ifdesired, the reaction may be carried out in an autoclave at an increasedpressure.

Compounds of formula (I) can also be prepared by reductively alkylatingan intermediate of formula (IV), wherein Alk¹′ represents a direct bondor C₁₋₅alkanediyl, following art-known reductive alkylation procedureswith an intermediate of formula (III).

Said reductive alkylation can be performed in a reaction-inert solventsuch as, for example, dichloromethane, ethanol, toluene or a mixturethereof, and in the presence of a reducing agent such as, for example, aborohydride, e.g. sodium borohydride, sodium cyanoborohydride ortriacetoxy borohydride. It may also be convenient to use hydrogen as areducing agent in combination with a suitable catalyst such as, forexample, palladium-on-charcoal, rhodium-on-carbon orplatinum-on-charcoal. In case hydrogen is used as reducing agent, it maybe advantageous to add a dehydrating agent to the reaction mixture suchas, for example, aluminium tert-butoxide. In order to prevent theundesired further hydrogenation of certain functional groups in thereactants and the reaction products, it may also be advantageous to addan appropriate catalyst-poison to the reaction mixture, e.g., thiopheneor quinoline-sulphur. To enhance the rate of the reaction, thetemperature may be elevated in a range between room temperature and thereflux temperature of the reaction mixture and optionally the pressureof the hydrogen gas may be raised.

Alternatively, compounds of formula (I) can also be prepared by reactingan acid chloride of formula (V), wherein Alk¹′ represents C₁₋₅alkanediylor a direct bond, with an intermediate of formula (III) under suitablereaction conditions.

Said reaction can be performed under hydrogenation conditions withhydrogen gas in the presence of a suitable catalyst such as, forexample, palladium-on-charcoal, rhodium-on-carbon orplatinum-on-charcoal, in a suitable solvent such as, for example, ethylacetate, and in the presence of magnesiumoxide. In order to prevent theundesired further hydrogenation of certain functional groups in thereactants and the reaction products, it may also be advantageous to addan appropriate catalyst-poison to the reaction mixture, e.g. thiopheneor quinoline-sulphur. To enhance the rate of the reaction, thetemperature may be elevated in a range between room temperature and thereflux temperature of the reaction mixture and optionally the pressureof the hydrogen gas may be raised.

Compounds of formula (I-a), defined as compounds of formula (I) whereinAlk² represents —CH₂—CHOH—CH₂—, can be prepared by reactingintermediates of formula (VI) with intermediates of formula (VII) in areaction-inert solvent, such as methanol, and optionally in the presenceof an organic base, such as triethyl amine.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions. For instance, compounds of formula (I) whereinR⁶ is phenylmethyl can be converted to the corresponding compounds offormula (I) wherein R⁶ is hydrogen by art-known debenzylationprocedures. Said debenzylation can be performed following art-knownprocedures such as catalytic hydrogenation using appropriate catalysts,e.g. platinum on charcoal, palladium on charcoal, in appropriatesolvents such as methanol, ethanol, 2-propanol, diethyl ether,tetrahydrofuran, and the like. Furthermore, compounds of formula (I)wherein R⁶ is hydrogen may be alkylated using art-known procedures suchas, e.g. reductive N-alkylation with a suitable aldehyde or ketone.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarbo-peroxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzene-carboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

The starting materials and some of the intermediates are known compoundsand are commercially available or may be prepared according toconventional reaction procedures generally known in the art. Forexample, a number of intermediates of formula (II) or (V) may beprepared according to art-known methodologies described in WO-93/17017and WO-95/053837.

Compounds of formula (I) and some of the intermediates may have one ormore stereogenic centers in their structure, present in a R or a Sconfiguration, such as, e.g. the carbon atom bearing the R⁴ substituent,and the carbon atom linked to the —Alk¹—NR⁶—Alk²—R⁵ moiety.

The compounds of formula (I) as prepared in the hereinabove describedprocesses may be synthesized in the form of racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. The racemic compounds of formula (I) may beconverted into the corresponding diastereomeric salt forms by reactionwith a suitable chiral acid. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali.An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography using a chiralstationary phase. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I), the N-oxide forms, the pharmaceuticallyacceptable salts and stereoisomeric forms thereof possess favourablefundic relaxation properties as evidenced in pharmacological exampleC-1, the “Gastric tone measured by an electronic barostat in consciousdogs”-test.

Furthermore, the compounds of the present invention have additionalbeneficial pharmacological properties in that they have little or novasoconstrictor activity as can be demonstrated in pharmacologicalexample C.2 “Vasoconstrictive activity on basilar artery”.Vasoconstrictor activity can cause undesirable side-effects such ascoronary effects which can induce chest pain.

In view of the capability of the compounds of the present invention torelax the fundus, the subject compounds are useful to treat conditionsrelated to a hampered or impaired relaxation of the fundus such as, e.g.dyspepsia, early satiety, bloating and anorexia.

Dyspepsia is described as a motility disorder. Symptoms can be caused bya delayed gastric emptying or by impaired relaxation of the fundus tofood ingestion. Warm-blooded animals, including humans, (generallycalled herein patients) suffering from dyspeptic symptoms as a result ofdelayed gastric emptying usually have a normal fundic relaxation and canbe relieved of their dyspeptic symptoms by administering a prokineticagent such as, e.g. cisapride. Patients can have dyspeptic symptomswithout having a disturbed gastric emptying. Their dyspeptic symptomsmay result from a hypercontracted fundus or hypersensitivity resultingin a diminished compliance and abnormalities in the adaptive fundicrelaxation. A hypercontracted fundus results in a diminished complianceof the stomach. The “compliance of the stomach” can be expressed as theratio of the volume of the stomach over the pressure exerted by thestomach wall. The compliance of the stomach relates to the gastric tone,which is the result of the tonic contraction of muscle fibers of theproximal stomach. This proximal part of the stomach, by exerting aregulated tonic contraction (gastric tone), accomplishes the reservoirfunction of the stomach.

Patients suffering from early satiety cannot finish a normal meal sincethey feel saturated before they are able to finish said normal meal.Normally when a subject starts eating, the stomach will show an adaptiverelaxation, i.e. the stomach will relax to accept the food that isingested. This adaptive relaxation is not possible when the complianceof the stomach is hampered which results in an impaired relaxation ofthe fundus.

In view of the utility of the compounds of formula (I), it follows thatthe present invention also provides a method of treating warm-bloodedanimals, including humans, (generally called herein patients) sufferingfrom impaired relaxation of the fundus to food ingestion. Consequently amethod of treatment is provided for relieving patients suffering fromconditions, such as, for example, dyspepsia, early satiety, bloating andanorexia.

Hence, the use of a compound of formula (I) as medicine is provided, andin particular the use of a compound of formula (I) for the manufactureof a medicine for treating conditions involving an impaired relaxationof the fundus to food ingestion. Both prophylactic and therapeutictreatment are envisaged.

The symptoms of impaired fundic relaxation may also arise due to theintake of chemical substances, e.g. Selective Seretonine Re-uptakeInhibitors (SSRI's), such as fluoxetine, paroxetine, fluvoxamine,citalopram and sertaline.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of (I) due to theirincreased water solubility over the corresponding base form, areobviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions may take theform of solid dose forms, for example, tablets (both swallowable-onlyand chewable forms), capsules or gelcaps, prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants e.g. magnesium stearate, talc or silica);disintegrants (e.g. potato starch or sodium starch glycollate); orwetting agents (e.g. sodium lauryl sulphate). The tablets may be coatedby methods well known in the art.

Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means,optionally with pharmaceutically acceptable additives such as suspendingagents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners comprise preferably at least oneintense sweetener such as saccharin, sodium or calcium saccharin,aspartame, acesulfame potassium, sodium cyclamate, alitame, adihydrochalcone sweetener, monellin, stevioside or sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose), preferablysaccharin, sodium or calcium saccharin, and optionally a bulk sweetenersuch as sorbitol, mannitol, fructose, sucrose, maltose, isomalt,glucose, hydrogenated glucose syrup, xylitol, caramel or honey.

Intense sweeteners are conveniently employed in low concentrations. Forexample, in the case of sodium saccharin, the concentration may rangefrom 0.04% to 0.1% (w/v) based on the total volume of the finalformulation, and preferably is about 0.06% in the low-dosageformulations and about 0.08% in the high-dosage ones. The bulk sweetenercan effectively be used in larger quantities ranging from about 10% toabout 35%, preferably from about 10% to 15% (w/v).

The pharmaceutically acceptable flavours which can mask the bittertasting ingredients in the low-dosage formulations are preferably fruitflavours such as cherry, raspberry, black currant or strawberry flavour.A combination of two flavours may yield very good results. In thehigh-dosage formulations stronger flavours may be required such asCaramel Chocolate flavour, Mint Cool flavour, Fantasy flavour and thelike pharmaceutically acceptable strong flavours. Each flavour may bepresent in the final composition in a concentration ranging from 0.05%to 1% (w/v). Combinations of said strong flavours are advantageouslyused. Preferably a flavour is used that does not undergo any change orloss of taste and colour under the acidic conditions of the formulation.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example as a sparingly soluble salt.

The compounds of the invention may be formulated for parenteraladministration by injection, conveniently intravenous, intramuscular orsubcutaneous injection, for example by bolus injection or continuousintravenous infusion. Formulations for injection may be presented inunit dosage form e.g. in ampoules or in multidose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as isotonizing, suspending, stabilising and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile pyrogen-freewater before use.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration the compounds of the invention may beused, for example, as a liquid spray, as a powder or in the form ofdrops.

The formulations of the present invention may optionally include ananti-flatulent, such as simethicone, alpha-D-galactosidase and the like.

In general it is contemplated that a therapeutically effective amountwould be from about 0.001 mg/kg to about 2 mg/kg body weight, preferablyfrom about 0.02 mg/kg to about 0.5 mg/kg body weight. A method oftreatment may also include administering the active ingredient on aregimen of between two or four intakes per day.

Experimental Part

In the procedures described hereinafter the following abbreviations wereused: “ACN” stands for acetonitrile and “DCM” stands fordichloromethane.

For some chemicals the chemical formula was used, e.g. CH₂Cl₂ fordichloromethane CH₃OH for methanol, NH₃ for ammonia, HCl forhydrochloric acid, and NaOH for sodium hydroxide.

In those cases the stereochemically isomeric form which was firstisolated is designated as “A”, the second as “B”, the third one as “C”and the fourth one as “D”, without further reference to the actualstereochemical configuration.

A. PREPARATION OF THE INTERMEDIATES EXAMPLE A.1

A reaction solution of 1-(2-propenyl)-2,4-imidazolidinedione (0.036 mol)and 3-chlorobenzenecarboperoxoic acid (0.043 mol, 70.75%) in DCM (25 ml)was stirred for 2 hours at room temperature. An aqueous solution ofbisulfite was added (to remove excess 3-chlorobenzenecarboperoxoic acid)and the mixture was stirred for 10 minutes. Na₂CO₃ was added and thismixture was extracted with DCM. The separated organic layer was dried,filtered and the solvent evaporated, yielding 5 g (89%) of(±)-1-(oxiranylmethyl)-2,4-imidazolidinedione (interm. 1).

EXAMPLE A.2

a) A solution of 2-hydroxypyrimidine hydrochloride (1:1) (0.075 mol) inmethanol (150 ml) was stirred for 30 minutes and then added to asolution of sodium carbonate (0.075 mol) in methanol (20 ml). Themixture was stirred and refluxed for 15 minutes, and cooled to 55° C. Asolution of N,N-bis(phenylmethyl)oxiranmethanamine (0.075 mol) intoluene (160 ml) was added dropwise and the reaction mixture was stirredat 50° C. overnight. Water (75 ml) was added and the mixture was stirredat 55° C. for 15 minutes. The organic layer was separated, washed withwater, dried, filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₃OH/CH₂Cl₂97/3). The pure fractions were collected and the solvent was evaporated,yielding 11.8 g (45%) of(±)-1-[3-[bis(phenylmethyl)amino]-2-hydroxypropyl]-2(1H)pyrimidinone(interm. 2).

b) A solution of intermediate (2) (0.034 mol) in methanol (500 ml) washydrogenated with palladium on activated carbon as a catalyst in thepresence of thiophene. After uptake of hydrogen (1 equivalent), thecatalyst was filtered off and the filtrate was evaporated. The residuewas purified by column chromatography over silica gel (eluent:CH₂Cl₂/(CH₃OH/NH₃) 95/5). The pure fractions were collected and thesolvent was evaporated, yielding 6.15 g (70%) oftetrahydro-1-[2-hydroxy-3-[(phenylmethyl)amino]propyl]-2(1H)pyrimidinone(interm. 3).

B. PREPARATION OF THE FINAL COMPOUNDS EXAMPLE B.1

3,4-Dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine (0.032 mol)in methanol (100 ml) was stirred at room temperature. A solution ofintermediate (1) (0.032 mol) in methanol (50 ml) was added dropwise andthe resulting reaction mixture was stirred overnight at roomtemperature. The solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃) 99/1).The desired fractions were collected and the solvent was evaporated,yielding 3.5 g (27%) of(±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)-amino]-2-hydroxypropyl]-2,4-imidazolidinedione(comp. 3).

EXAMPLE B.2

A mixture of 3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde, (0.023 mol)and intermediate (3) (0.023 mol) in methanol (250 ml) was hydrogenatedwith palladium on activated carbon (10%) as a catalyst in the presenceof thiophene. After uptake of hydrogen (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 99/1). Thepure fractions were collected and the solvent was evaporated, yielding5.9 g (62%) of(±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]-2-hydroxypropyl]tetrahydro-2(1H)pyrimidinone(comp. 1).

EXAMPLE B.3

A mixture of compound (3) (0.0086 mol) in methanol (100 ml) washydrogenated at 25° C. with palladium on activated carbon (1 g) as acatalyst. After uptake of hydrogen (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was dissolvedin ACN and converted into the hydrochloric acid salt (1:1) withHCl/2-propanol. The precipitate was filtered off and dried, yielding0.49 g of(±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-2-hydroxypropyl]-2,4-imidazolidinedionemonohydrochloride (comp. 4).

EXAMPLE B.4

a) A solution of 2-hydroxypyrimidine (0.16 mol) in methanol (300 ml) wasstirred at room temperature for 30 minutes. A solution of Na₂CO₃ (0.16mol) in methanol (40 ml) was added. The mixture was stirred and refluxedfor 15 minutes and cooled to 55° C. A solution ofN,N-bis(phenylmethyl)-2-oxiranemethanamine (0.16 mol) in toluene (320ml) was added dropwise. The mixture was stirred at 50° C. overnightWater (150 ml) was added The mixture was stirred at 55° C. for 15minutes. The organic layer was separated, washed with water, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 97/3). Thepure fractions were collected and the solvent was evaporated, yielding26.55 g of(±)-[3-[bis(phenylmethyl)amino]-2-hydroxypropyl]-2(1H)pyrimidinone(intermediate 4).

b) A mixture of intermediate (4) (0.073 mol) in HCl/2-propanol (20 ml)and CH₃OH (250 ml) was hydrogenated with Pd/C 10% (2 g) as a catalyst.After uptake of hydrogen (3 equivalents), the catalyst was filtered offand the filtrate was evaporated. The residue was separated into itsenantiomers by HPLC (eluent: hexane/EtOH 50/50; Chiralpak AD 1000 Å 20μm). The pure fractions were collected and the solvent was evaporated,yielding 4 g of(A)-tetrahydro-1-[2-hydroxy-3-[(phenylmethyl)amino]propyl]-2(1H-pyrimidinone(intermediate 5).

c) A mixture of [S-(R*,R*)]-3,4-dihydro-2-oxiranyl-2H-1-benzopyran(0.006 mol) and intermediate (5) (0.006 mol) in ethanol (25 ml) wasstirred and refluxed for 2 hours. The solvent was evaporated and theresidue was purified by HPLC (eluent: hexane/ethanol 70/30; Chiralcel OJ20 μm). The pure fractions were collected and the solvent wasevaporated, yielding 1.7 g of[S(A)]-1-[3-[[2-(3,4-dihydro-2H-1-benzopyran-2-yl)-2-hydroxyethyl](phenylmethyl)amino]-2-hydroxypropyl]tetrahydro-2(1H)-pyrimidinone(intermediate 6).

d) A mixture of intermediate (6) (0.004 mol) in CH₃OH (100 ml) washydrogenated with Pd/C 10% (0.5 g) as a catalyst. After uptake ofhydrogen (1 equivalent), the catalyst was filtered off. The reactionmixture was converted into the hydrochloric acid salt (1:1) withHCl/2-propanol. DIPE was added. The precipitate was filtered off anddried, yielding 0.69 g of[S(A)]-1-[3-[[2-(3,4-dihydro-2H-1-benzopyran-2-yl)2-hydroxyethyl]amino]-2-hydroxypropyl]tetrahydro-2(1H)-pyrimidinonemonohydrochloride dihydrate (mp. 138° C.) (compound 15).

Table F-1 and F-2 list the compounds that were prepared according to oneof the above Examples and table F.3 lists both the experimental (columnheading “exp.”) and theoretical (column heading “theor.”) elementalanalysis values for carbon, hydrogen and nitrogen of some of thecompounds as prepared in the experimental part hereinbove.

TABLE F-1

Co Ex. Physical data No. No. R⁶ —Alk²—R⁵ (mp. in ° C.) 1 B.2 —CH₂—C₆H₅

— 2 B.3 H

.HCl (1:2) 3 B.1 —CH₂—C₆H₅

— 4 B.3 H

.HCl (1:1) 5 B.3 H

(A); .HCl (1:2) 6 B.3 H

(B); .HCl (1:1) 7 B.3 H

(C); .HCl (1:2) 8 B.3 H

(D); .HCl (1:1) .H₂O (1:0) 13 B.1 —CH₂—C₆H₅

(R); .HCl (1:1) 14 B.3 H

(R); .HCl (1:1); mp. 241° C.; [α]_(D) ²⁰ = −75.62°, c = 4.95 mg/ml inCH₃OH .C₂H₂O₄ stands for the ethanedioate salt

TABLE F-2

Co Ex. Physical data No. No. R⁶ -Alk²-R⁵ (mp. in ° C.) 9 B.1 —CH₂—C₆H₅

.HCl (1:1) 10 B.3 H

.HCl (1:1) 11 B.2 —CH₂—C₆H₅

— 12 B.3 H

—

TABLE F-3 Co. Carbon Hydrogen uz,23/32 Nitrogen No. Exp. Theor. Exp.Theor. Exp. Theor. 2 53.30 52.05 7.11 6.94 11.04 10.71 4 52.82 54.015.95 6.23 11.34 11.81 5 53.29 52.04 7.60 6.94 10.32 10.71 6 53.94 57.387.34 7.36 11.06 11.81 7 52.85 52.04 7.90 6.94 10.15 10.71 8 53.22 54.617.65 7.55 10.87 11.24 10 53.52 54.01 6.14 6.23 11.63 11.81 12 57.4457.38 7.31 7.36 11.61 11.81

C. PHARMACOLOGICAL EXAMPLES C.1. Gastric Tone Measured by an ElectronicBarostat in Conscious Dogs

Gastric tone cannot be measured by manometric methods. Therefore anelectronic barostat was used. This allows the study of the physiologicalpattern and regulation of gastric tone in conscious dogs and theinfluence of test-compounds on this tone.

The barostat consists of an air injection system which is connected by adouble-lumen 14-French polyvinyl tube to an ultrathin flaccidpolyethylene bag (maximal volume: ±700 ml). Variations in gastric tonewere measured by recording changes in the volume of air within anintragastric bag, maintained at a constant pressure. The barostatmaintains a constant pressure (preselected) within a flaccid air-filledbag introduced into the stomach, changing the volume of air within thebag by an electronic feedback system.

Thus, the barostat measures gastric motor activity (contraction orrelaxation) as changes in intragastric volume (decrease or increaseresp.) at a constant intragastric pressure. The barostat consists of astrain gauge linked by an electronic relay to an airinjection-aspiration system. Both the strain gauge and the injectionsystem are connected by means of double-lumen polyvinyl tube to anultrathin polyethylene bag. A dial in the barostat allows selection ofthe pressure level to be maintained within the intragastric bag.

Female beagle dogs, weighing 7-17 kg, were trained to stand quietly inPavlov frames. They were implanted with a gastric cannula under generalanaesthesia and aseptic precautions. After a median laparotomy, anincision was made through the gastric wall in longitudinal directionbetween the greater and the lesser curve, 2 cm above the nerves ofLatarjet. The cannula was secured to the gastric wall by means of adouble purse string suture and brought out via a stub wound at the leftquadrant of the hypochondrium. Dogs were allowed a recovery period oftwo weeks.

At the beginning of the experiment, the cannula was opened in order toremove any gastric juice or food remnants. If necessary, the stomach wascleansed with 40 to 50 ml lukewarm water. The ultrathin bag of thebarostat was positioned into the fundus of the stomach through thegastric cannula. In order to ensure easy unfolding of the intragastricbag during the experiment, a volume of 300-400 ml was injected twiceinto the bag.

When during a stabilisation period of maximum 90 minutes, the gastricvolume is stable during 15 minutes at a constant pressure of 6 mmHg(about 0.81 kPa), the test compound was administered subcutaneously(S.C.), or intraduodenally (I.D.). Test compounds were screened, i.e.changes in gastric volume were measured, usually at 0.63 mg/kg. Otherdoses and routes were tested if a test compound was shown to be activeduring the screening procedure. Table C-1 summarizes the mean maximalchange in volume on relaxation of the fundus, during the 1 hourobservation period after S.C. or I.D. administration of the testcompound (0.63 mg/kg).

TABLE C-1 Maximum change Maximum change Co. No. Route in volume (ml) Co.No. Route in volume (ml) 5 S.C. 41 14 I.D. 144 6 S.C. 146 14 S.C. 90 7S.C. 34 15 I.D. 5

C.2 Vasoconstrictive Activity on Basilar Artery

Segments of basilar arteries taken from pigs (anaesthetised with sodiumpentobarbital) were mounted for recording of isometric tension in organbaths. The preparations were bathed in Krebs-Henseleit solution. Thesolution was kept at 37° C. and gassed with a mixture of 95% O₂-5% CO₂.The preparations were stretched until a stable basal tension of 2 gramswas obtained.

The preparations were made to constrict with serotonin (3×10⁻⁷ M). Theresponse to the addition of serotonin was measured and subsequently theserotonin was washed away. This procedure was repeated until stableresponses were obtained. Subsequently the test compound was administeredto the organ bath and the constriction of the preparation was measured.This constrictive response was expressed as a percentage of the responseto serotonin as measured previously.

The ED₅₀-value (molar concentration) is defined as the concentration atwhich a test compound causes 50% of the constrictive response obtainedwith serotonin. Said ED₅₀-values are estimated from experiments on threedifferent preparations.

1. A compound of formula (I)

a stereochemically isomeric form thereof, an N-oxide form thereof, apharmaceutically acceptable acid addition salt thereof, or a quaternaryammonium salt thereof wherein Alk¹ is C₁₋₄alkylcarbonyl,C₁₋₄alkylcarbonylC₁₋₄alkyl, carbonyl, carbonylC₁₋₄alkyl orC₁₋₆alkanediyl optionally substituted with hydroxy, halo, amino,hydroxyC₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyloxyC₁₋₄alkyl,C₁₋₄alkylcarbonyloxy, C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, orC₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy; Alk² isC₁₋₄alkylcarbonylC₁₋₄alkyl; C₁₋₆alkanediyl substituted with hydroxy,halo, amino, hydroxyC₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyloxyC₁₋₄alkyl,C₁₋₄alkyloxycarbonyloxyC₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, orC₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy; C₃₋₈cycloalkanediyloptionally substituted with halo, hydroxy, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxy, C₁₋₄alkyloxy₁₋₄alkyl, C₁₋₄alkyloxycarbonyl,C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, orC₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy; —Z¹—Z²— is a bivalentradical of formula—O—CH(R⁴)—CH₂—CH₂—  (a-4),—O—C(R⁴)═CH—CH₂—  (a-7),—O—CH(R⁴)—CH═CH—  (a-9), wherein optionally one or two hydrogen atoms onthe same or a different carbon atom may be replaced by hydroxy; R¹, R²and R³ are each independently selected from hydrogen, C₁₋₆alkyl,C₃₋₆alkenyl, C₁₋₆alkyloxy, trihalomethyl, trihalomethoxy, halo, hydroxy,cyano, nitro, amino, C₁₋₆alkylcarbonylamino, C₁₋₆alkyloxycarbonyl,C₁₋₄alkylcarbonyloxy, aminocarbonyl mono- or di(C₁₋₆alkyl)aminocarbonyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,C₁₋₄alkylcarbonyloxy-C₁₋₄alkyloxycarbonyloxy, orC₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxy-carbonyloxy; or when R¹ and R² areon adjacent carbon atoms, R¹ and R² taken together may form a bivalentradical of formula —CH₂—CH₂—CH₂— (b-1), —CH₂—CH₂—CH₂—CH₂— (b-2),—CH₂—CH₂—CH₂—CH₂—CH₂— (b-3), —CH═CH—CH═CH— (b-4), —O—CH₂—O— (b-5),—O—CH₂—CH₂— (b-6), —O—CH₂—CH₂—O— (b-7), —O—CH₂—CH₂—CH₂— (b-8),—O—CH₂—CH₂—CH₂—CH₂— (b-9),

wherein optionally one or two hydrogen atoms on the same or a differentcarbon atom may be replaced by hydroxy, C₁₋₄alkyl or CH₂OH; R⁴ ishydrogen, C₁₋₆alkyl, phenylmethyl, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl,C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyl,C₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy, or a direct bond whenthe bivalent radical —Z¹—Z²— is of formula (a-7); R⁶ is hydrogen,C₁₋₆alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, phenylmethyl,C₁₋₄alkylaminocarbonyl, C₁₋₄alkylcarbonyloxyC₁₋₄alkyloxycarbonyl, orC₃₋₆cycloalkylcarbonyloxyC₁₋₄alkyloxycarbonyloxy; R⁵ is a radical offormula

wherein n is 1 or 2; p¹ is 0, and p² is 1 or 2; or p¹ is 1 or 2, and p²is 0; X is oxygen, sulfur, NR⁹ or CHNO₂; Y is oxygen or sulfur; R⁷ ishydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl or phenylmethyl; R⁸ isC₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl or phenylmethyl; R⁹ is cyano,C₁₋₆alkyl C₃₋₆cycloalkyl, C₁₋₆alkyloxycarbonyl or aminocarbonyl; R¹⁰ ishydrogen or C₁₋₆alkyl; or R⁹ and R¹⁰ taken together with the nitrogenatom to which they are attached may form a pyrrolidinyl, piperidinyl,homopiperidinyl, piperazinyl, or morpholinyl group, optionallysubstituted with C₁₋₄alkyl or C₁₋₄alkyloxy; and Q is a bivalent radicalof formula —CH₂—CH₂— (d-1), or —CO—CH₂— (d-6), —CH═CH— (d-4), —CH₂—CO—(d-5),

wherein optionally one or two hydrogen atoms on the same or a differentcarbon atom may be replaced by C₁₋₄alkyl, hydroxy or phenyl.
 2. Acompound as claimed in claim 1 wherein R⁵ is a radical of formula (c-1)wherein X is oxygen, and Q is a radical of formula (d-5).
 3. A compoundaccording to claim 1 wherein R⁴ is hydrogen, Alk¹ is —CH₂—, Alk² is—CH₂—CHOH—CH₂—, R⁶ is hydrogen, R⁵ is a radical of formula (c-1) whereinX is oxygen, R⁷ is hydrogen, and Q is (d-5).
 4. A compound according toclaim 1 wherein the compound is1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-2-hydroxypropyl]-2,4-imidazolidinedione;a stereoisomeric form or a pharmaceutically acceptable acid additionsalt thereof.
 5. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically active amountof a compound as claimed in claim
 1. 6. A process for preparing apharmaceutical composition wherein a therapeutically active amount of acompound as claimed in claim 1 is mixed with a pharmaceuticallyacceptable carrier.
 7. A process for preparing a compound of formula (I)wherein a) an intermediate of formula (II) is alkylated with anintermediate of formula (III) in a reaction-inert solvent and,optionally in the presence of a suitable base,

b) an intermediate of formula (IV), wherein Alk¹′ represents a directbond or C₁₋₅alkanediyl, is reductively alkylated with an intermediate offormula (III);

c) an intermediate of formula (VI) is reacted with an intermediate offormula (VII) thus yielding compounds of formula (I-a), defined ascompounds of formula (I) wherein Alk² represents —CH₂—CHOH—CH₂—;

in the above reaction schemes the radicals —Z¹—Z²—, R¹, R², R³, R⁴, R⁵,R⁶, Alk¹ and Alk² are as defined in claim 1 and W is an appropriateleaving group; d) or, compounds of formula (I) are converted into eachother following art-known transformation reactions; or if desired; acompound of formula (I) is converted into an acid addition salt, orconversely, an acid addition salt of a compound of formula (I) isconverted into a free base form with alkali; and, if desired, preparingstereochemically isomeric forms thereof.
 8. A method of treatingconditions involving an impaired relaxation of the fundus comprisingadministering to a subject in need thereof an effective amount of acompound of claim 1.